Discovery of the disorder started from a deduction: Researchers knew the gene's function, so they hypothesized how mutations would affect cholesterol levels, vulnerability to gallstones and other factors. They then searched a genetic database of some 12,000 patients and identified a number of people who had mutations in that gene. They studied the family of one patient and found that carriers of mutations in the gene did indeed have elevated cholesterol, including three siblings with dangerously elevated levels.
"We went from a hypothesis to identifying the disorder in patients, rather than the more conventional route of seeing a disorder in patients and searching for the cause," said John Kane, MD, PhD, UCSF professor of medicine and senior author of a report on the findings in the July issue of The Journal of Clinical Investigation.
"Our finding adds to the roster of genes that can cause a disorder of cholesterol in the blood and increase the risk of heart disease and stroke," Kane said. "By understanding the mechanism how this gene affects cholesterol regulation we can diagnose those at risk earlier and choose better treatments for them."
The research is highlighted in an accompanying editorial in the journal by scientists from the Gladstone Institute of Cardiovascular Disease, UCSF and UC San Diego.
The discovery is the fifth gene known to cause elevated cholesterol when it is defective. The gene's product is an enzyme called cholesterol 7-alpha hydroxylase (CYP7A1), and it is essential for the normal elimination of cholesterol. The enzyme initiates the primary conversion of cholesterol into bile acids in the liver.